Differential virological and immunological outcome of severe acute respiratory syndrome coronavirus infection in susceptible and resistant transgenic mice expressing human angiotensin-converting enzyme 2.

Abstract

We previously reported that transgenic (Tg) mice expressing human angiotensin-converting enzyme 2 (hACE2), the receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), were highly susceptible to SARS-CoV infection, which resulted in the development of disease of various severity and even death in some lineages. In this study, we further characterized and compared the pathogeneses of SARS-CoV infection in two of the most stable Tg lineages, AC70 and AC22, representing those susceptible and resistant to the lethal SARS-CoV infection, respectively. The kinetics of virus replication and the inflammatory responses within the lungs and brains, as well as the clinical and pathological outcomes, were assessed in each lineage. In addition, we generated information on lymphocyte subsets and mitogen-mediated proliferation of splenocytes. We found that while both lineages were permissive to SARS-CoV infection, causing elevated secretion of many inflammatory mediators within the lungs and brains, viral infection appeared to be more intense in AC70 than in AC22 mice, especially in the brain. Moreover, such infection was accompanied by a more profound immune suppression in the former, as evidenced by the extensive loss of T cells, compromised responses to concanavalin A stimulation, and absence of inflammatory infiltrates within the brain. We also found that CD8(+) T cells were partially effective in attenuating the pathogenesis of SARS-CoV infection in lethality-resistant AC22 mice. Collectively, our data revealed a more intense viral infection and immunosuppression in AC70 mice than in AC22 mice, thereby providing us with an immunopathogenic basis for the fatal outcome of SARS-CoV infection in the AC70 mice.

• Authors: Naoko Yoshikawa, Tomoki Yoshikawa, Terence Hill, Cheng Huang, Douglas M Watts, Shinji Makino, Gregg Milligan, Tehsheng Chan, Clarence J Peters, Chien-Te K Tseng
• Journal: Journal of virology (J Virol) Vol. 83 Issue 11 Pg. 5451-65 (Jun 2009) ISSN: 1098-5514 [Electronic] United States
• PMID: 19297479 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Concanavalin A
• Peptidyl-Dipeptidase A
• ACE2 protein, human
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2

Topics

• Angiotensin-Converting Enzyme 2
• Animals
• Brain Diseases (virology)
• Cell Proliferation (drug effects)
• Concanavalin A (pharmacology)
• Cytokines (immunology)
• Gene Expression Regulation, Enzymologic
• Genetic Predisposition to Disease (genetics)
• Humans
• Kinetics
• Lung Diseases (virology)
• Lymphocytes (cytology, drug effects, immunology)
• Mice
• Mice, Transgenic
• Organ Specificity
• Peptidyl-Dipeptidase A (genetics, metabolism)
• Severe acute respiratory syndrome-related coronavirus (immunology)
• Severe Acute Respiratory Syndrome (immunology, metabolism, pathology, virology)
• Spleen (cytology, drug effects, immunology)
• Virus Replication